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    Clinical Trial Results:
    Induction chemotherapy with cetuximab-docetaxel-cisplatin-fluorouracil (ETPF) in patients with resectable stage III or IV squamous cell carcinoma of the oropharynx

    Summary
    EudraCT number
    		 2007-002116-25
    Trial protocol
    		 FR  
    Global end of trial date
    30 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jul 2016
    First version publication date
    23 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    O 07-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00665392
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GERCOR
    Sponsor organisation address
    151 rue du faubourg Saint Antoine, PARIS, France, 75011
    Public contact
    Regulatory Affairs, GERCOR, 33 1 49 29 85 00, regulatory.affairs@gercor.com.fr
    Scientific contact
    Coordinating investigator - Tenon Hospital - Paris, Pr Jean Lacau St Guily , 33 1 40 29 85 00, regulatory.affairs@gercor.com.fr
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Apr 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the clinical and radiological complete response (crCR) of the primary tumor at 3 months after cetuximab-TPF combination (ETPF) induction therapy in the treatment of patients with locally advanced resectable SCCHN of the oropharynx.
    Protection of trial subjects
    Pre and concomitant medication consisted of IV hydration and infusion of diphenhydramine hydrochloride and dexamethasone, oral corticoid, antiemetic and IV antihistaminic. Primary prophylaxis with granulocyte colony stimulating factor (G-CSF) was required. In case of allergic reaction to cetuximab, or hematological events or other adverse events, doses were to be reduced. Dose adjustments were to be made according to the system showing the greatest degree of toxicity.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jul 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 42
    Worldwide total number of subjects
    42
    EEA total number of subjects
    42
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    37
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From July 2008 to April 2013, 42 were included in 9 french centers were active (APHP : Tenon, HEGP, Bichat - Paris; Centre René Huguenin - Saint Cloud; Hôpital Foch - Suresnes; GH Saint Joseph - Paris; Hôpital Simone Veil - Montmorency; CH Lyon Sud - Lyon ; Hôpital Delafontaine - Saint Denis.

    Pre-assignment
    Screening details
    		 The main inclusion criteria : Previously untreated, resectable stage III (T3 or T1-2N1-2M0) to IVB (T4 or T1-3N3M0) SCCHN of the oropharynx, measurable or evaluable disease, WHO performance status ≤1, adequate hematologic, renal and liver functions. The main exclusion criteria: Uncontrolled cardiac or other disease, Hearing impairment

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 ETPF administration
    Arm description
    		 Erbitux with concomitant anti-tumor therapy : TPF (Taxotere, Cisplatin, 5FU) 3 cycles (one cycle = 21 days )
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cetuximab
    Investigational medicinal product code
    Other name
    Erbitux
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    cetuximab : IV infusion during 120 min dosage: 400 mg/m² Day 1, 250 mg/m² Day 8 and Day 15.

    Investigational medicinal product name
    Docetaxel
    Investigational medicinal product code
    Other name
    Taxotere
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Taxotere :IV infusion 1h Dosage : 75mg/m² Day 1

    Investigational medicinal product name
    Cisplatin
    Investigational medicinal product code
    Other name
    Cisplatine
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cisplatin: IV infusion 1h dosage: 75mg/m² Day 1

    Investigational medicinal product name
    5 FU
    Investigational medicinal product code
    Other name
    Fluoro-uracile
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    5FU : IV infusion on 5 days Dosage : 750mg/m²/day = 3750mg/m² total dose

    Number of subjects in period 1
    		ETPF administration
    Started
    42
    Completed
    40
    Not completed
    2
         toxic death
    1
         Protocol deviation
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Period
    Reporting group description
    		 ETPF administration

    Reporting group values
    		 Overall Period Total
    Number of subjects
    		 42 42
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 37 37
        From 65-84 years
    		 5 5
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 56.1 ± 6.8 -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 34 34
    grade of differentiation
    Units: Subjects
        Well
    		 17 17
        Moderate
    		 18 18
        Poor or undifferentiated
    		 4 4
        Missing
    		 3 3
    Primary tumor localization
    Units: Subjects
        Anterior
    		 3 3
        Lateral (tonsillar area)
    		 37 37
        Posterior
    		 1 1
        Superior
    		 1 1
    T-stage
    Units: Subjects
        T2
    		 13 13
        T3
    		 24 24
        T4
    		 5 5
    N-stage
    Units: Subjects
        N0
    		 5 5
        N1
    		 9 9
        N2
    		 27 27
        N3
    		 1 1
    Staging
    Units: Subjects
        III
    		 32 32
        IV
    		 10 10
    ECOG status
    Units: Subjects
        PS 0
    		 33 33
        PS 1
    		 8 8
        Missing
    		 1 1
    Lip mobility
    Units: Subjects
        Normal
    		 40 40
        Decreased
    		 2 2
    Trismus
    Units: Subjects
        Yes
    		 5 5
        No
    		 37 37
    Creatinine clearance (ml/min)
    Units: Subjects
        < 60
    		 1 1
        60 - 120
    		 31 31
        > 120
    		 8 8
        Missing
    		 2 2
    Albuminemia (g/L)
    Units: Subjects
        < 40
    		 8 8
        ≥60
    		 14 14
        Missing
    		 20 20
    Life style risk factor
    Units: Subjects
        Alcohol
    		 3 3
        Tobacco
    		 8 8
        Alcohol + Tobacco
    		 25 25
        None
    		 6 6
    HPV16 status
    Units: Subjects
        Positive
    		 17 17
        Negative
    		 25 25

    End points

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    End points reporting groups
    Reporting group title
    ETPF administration
    Reporting group description
    		 Erbitux with concomitant anti-tumor therapy : TPF (Taxotere, Cisplatin, 5FU) 3 cycles (one cycle = 21 days )

    Subject analysis set title
    Tumor response rate - Tumor
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    At 3 months

    Subject analysis set title
    Tumor response rate - Node
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    At 3 months

    Subject analysis set title
    Tumor response rate - Tumor and node
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    At 3 months

    Subject analysis set title
    HPV16-positive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    17 patients/42 were HPV16-positive

    Subject analysis set title
    HPV-16 negative
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    25 patients/42 were HPV-16 negative

    Primary: Clinical and radiological complete response (crCR) of the primary tumor at 3 months

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    End point title
    		 Clinical and radiological complete response (crCR) of the primary tumor at 3 months [1]
    End point description
    Analyses were performed in a modified intent-to-treat (mITT) population. Patients were considered evaluable for tumor response if they had received at least one dose of ETPF combination.
    End point type
    Primary
    End point timeframe
    At 3 months after end of 3 cycles EPTF combination
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Response rate presented with corresponding 95% CI was calculated using the binomial distribution
    End point values
    		 Tumor response rate - Tumor Tumor response rate - Node Tumor response rate - Tumor and node
    Number of subjects analysed
    41
    41
    41
    Units: Subject
        complete (crCR)
    9
    8
    4
        incomplete
    29
    27
    31
        progression
    0
    0
    0
        not evaluable
    3
    6
    6
    No statistical analyses for this end point

    Secondary: Clinical Response (cR)

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    End point title
    		 Clinical Response (cR)
    End point description
    Clinical complete response (cCR) is defined by: • Disappearance of all clinical evidence of visible tumor, • Disappearance of all palpable residual infiltration, • Disappearance of all evidence of residual visible tumor on CT scan in pharynx and parapharyngeal space, • Complete symmetric remobilization of the tongue and amygdala. • Disappearance of pre-existing trismus. • Negative control biopsy.
    End point type
    Secondary
    End point timeframe
    at 3 months after end of 3 cycles ETPF combination
    End point values
    		 Tumor response rate - Tumor Tumor response rate - Node Tumor response rate - Tumor and node
    Number of subjects analysed
    41
    41
    41
    Units: number
        complete (cCR)
    17
    15
    13
        incomplete
    21
    23
    25
        progression
    0
    0
    0
        not evaluable
    3
    3
    3
    No statistical analyses for this end point

    Secondary: Radiological response (rR)

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    End point title
    		 Radiological response (rR)
    End point description
    Radiological response is defined according to RECIST 1.0 criteria: • Complete response (CR): disappearance of all target lesions • Partial response (PR): at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter, • Progressive disease (PD): at least a 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum longest diameter recorded since the treatment started or the appearance of one or more new lesions, • Stable disease (SD): neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum longest diameter since the treatment started
    End point type
    Secondary
    End point timeframe
    At 3 months after end of 3 cycles ETPF combination
    End point values
    		 Tumor response rate - Tumor Tumor response rate - Node Tumor response rate - Tumor and node
    Number of subjects analysed
    41
    41
    41
    Units: number
        complete (rCR)
    14
    8
    4
        Major Partial Response (≥50%)
    10
    14
    11
        Minor Partial Response (<50%)
    0
    3
    3
        Stable disease
    6
    6
    10
        Progression
    0
    0
    0
        Not evaluable
    11
    10
    13
    No statistical analyses for this end point

    Secondary: 2-year estimated PFS

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    End point title
    		 2-year estimated PFS
    End point description
    After a median of 23.9 months (95% CI, 15.4-28.6), median PFS was 37.6 months (95% CI, 19.1-NA)
    End point type
    Secondary
    End point timeframe
    2-year
    End point values
    		 ETPF administration
    Number of subjects analysed
    41
    Units: percentage
        median (standard error)
    63.6 ± 8.2
    No statistical analyses for this end point

    Secondary: 2-year estimated overall survival (OS)

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    End point title
    		 2-year estimated overall survival (OS)
    End point description
    Median OS was not achieved
    End point type
    Secondary
    End point timeframe
    2-year
    End point values
    		 ETPF administration
    Number of subjects analysed
    41
    Units: percentage
    median (standard error)
        2-year estimated OS
    82.4 ± 6.6
    No statistical analyses for this end point

    Secondary: Pathological response

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    End point title
    		 Pathological response
    End point description
    A pathological complete response is defined as no viable tumour cells detected on histological examination post surgery.
    End point type
    Secondary
    End point timeframe
    Pathological response is evaluable in patients with tumour surgical resection only.
    End point values
    		 ETPF administration
    Number of subjects analysed
    22
    Units: number
        pathological complete response
    9
    No statistical analyses for this end point

    Other pre-specified: Biomarkers analysis - EGFR pathway components

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    End point title
    		 Biomarkers analysis - EGFR pathway components
    End point description
    Biomarker levels analysis according to crCR in the patients for whom pre-treatment formalin-fixed, paraffin-embedded tumor tissue block and cryopreserved tumor blocks were available
    End point type
    Other pre-specified
    End point timeframe
    Correlative studies investigating EGFR-related biomarkers and HPV status in tumor and blood samples obtained prior to and after induction therapy were done for exploratory purposes as planned in the protocol
    End point values
    		 ETPF administration
    Number of subjects analysed
    38
    Units: number
        median (full range (min-max))
    0 (0 to 0)
    Attachments
    		 Untitled (Filename: ECHO 07_Biomarker levels analysis.pdf)
    No statistical analyses for this end point

    Other pre-specified: Biomarkers analysis - distribution of alcohol and tobacco use according to HPV status

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    End point title
    		 Biomarkers analysis - distribution of alcohol and tobacco use according to HPV status
    End point description
    End point type
    Other pre-specified
    End point timeframe
    HPV status in tumor and blood samples obtained prior to and after induction therapy were done for exploratory purposes as planned in the protocol.
    End point values
    		 HPV16-positive HPV-16 negative
    Number of subjects analysed
    17
    25
    Units: number
        Alcohol only
    2
    1
        Tobacco only
    5
    3
        Both Alcohol and Tobacco
    8
    17
        None
    2
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Until 1 month after the last administration
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    ETPF administration
    Reporting group description
    		 Erbitux with concomitant anti-tumor therapy : TPF (Taxotere, Cisplatin, 5FU)

    Serious adverse events
    		 ETPF administration
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 41 (31.71%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Vascular disorders
    Hypovolaemia
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
    Additional description: grade 3
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Acute pancreatitis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Febrile aplasia
         subjects affected / exposed
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection at the portacath site
         subjects affected / exposed
    2 / 41 (4.88%)
         occurrences causally related to treatment / all
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 ETPF administration
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 41 (100.00%)
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    18 / 41 (43.90%)
         occurrences all number
    0
    Anemia
         subjects affected / exposed
    33 / 41 (80.49%)
         occurrences all number
    0
    Thrombocytopenia
         subjects affected / exposed
    9 / 41 (21.95%)
         occurrences all number
    0
    Creatinine
         subjects affected / exposed
    9 / 41 (21.95%)
         occurrences all number
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    16 / 41 (39.02%)
         occurrences all number
    0
    Vomiting
         subjects affected / exposed
    13 / 41 (31.71%)
         occurrences all number
    0
    Stomatitis
         subjects affected / exposed
    14 / 41 (34.15%)
         occurrences all number
    0
    Diarrhoea
         subjects affected / exposed
    27 / 41 (65.85%)
         occurrences all number
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    18 / 41 (43.90%)
         occurrences all number
    0
    Infections and infestations
    Febrile neutropenia
         subjects affected / exposed
    8 / 41 (19.51%)
         occurrences all number
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Some data which reported as "not available" in the clinical study report have been reported as "0" in this register.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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